Full title: William M Feinberg Award for Excellence in Clinical Stroke:

Small vessel disease; a big problem, but fixable

108 char

Author: Joanna M Wardlaw, FRCR, MD

Affiliation: Division of Neuroimaging Science, Centre for Clinical Brain Science, Edinburgh

Imaging and UK Dementia Research Institute at the University of Edinburgh,

Address: Centre for Clinical Brain Science, Chancellor’s Building, 49 Little France Crescent,

Edinburgh, EH16 4SB, UK.

Tel: +44 (0)131 465 9599

Email: Joanna.wardlaw@ed.ac.uk

Cover title: Small vessel disease; a big problem, but fixable 48 char

Total tables and figures: no tables, 2 figures.

Key words: stroke; cerebral infarction: lacunar; lacunes; white matter disease; cerebral small

vessel disease; blood-brain barrier; cerebral blood flow.

Subject terms: lacunar stroke; small vessel disease; stroke; dementia; blood-brain barrier.

Word count: text 2956, whole document 4993, references 57.

1

Like much in stroke, this research journey started with a clot. Although this clot, and this

stroke, were different.1

Small vessel disease (SVD) is now recognised to cause 20-25% of strokes, to be the second

commonest cause of dementia, to cause cognitive decline, physical frailty and late onset

depression. In addition to acute small subcortical (lacunar) ischaemic strokes, SVD includes

lesions seen commonly on brain imaging: white matter hypertensities (WMH), lacunes,

microbleeds, perivascular spaces (PVS), brain shrinkage,2 and biomarkers in apparently

normal areas (e.g. increased tissue fluid volume and mobility).3 However, when this research

started, the strokes, cognitive presentations and neuroimaging features of SVD were thought

generally to be unrelated, silent, permanent, and lacunar stroke was a ‘small’ version of

large artery stroke.

How did it start? In 2000 A.D., a 70-year-old man presented to our hospital with a recent lacunar stroke. His

CT scan showed a small, low attenuation area, consistent with a recent small subcortical

(lacunar) infarct. There were three odd features.

1. In the centre was a small white dot, like a ‘mini’ version of the hyperattenuated middle

cerebral artery (MCA) commonly seen in patients with hyperacute cardio- or athero-

thromboembolic ischemic stroke, an appearance not described previously.

2. Brain MRI immediately after the CT scan confirmed the recent lacunar infarct including

the odd central line/dot, except that there also appeared to be some blood in the arteriole

wall. While a few small cardiac or carotid atheromatous emboli can enter the basal

perforating arterioles, about 6% in experimental models,4 and no more than 11% in

patients,5 an embolus would not explain the blood in the arteriole wall.

3. The ‘infarct’ was around the affected arteriolar segment, not at the end of it, as would be

expected in, e.g., an infarct occurring secondary to an acute MCA occlusion.

What was going on? Most strokes are thought to result from blocked or bleeding vessels. The thrombus in the

arteriole lumen, the wall abnormality and the ‘infarct’ location suggested some different

process. Was the surrounding tissue change ‘ischaemic’ or another process? And what were

the implications for other small subcortical lesions commonly seen in stroke, particularly in

lacunar stroke,2 such as WMH? Then, and now, WMH are commonly labelled ‘ischaemic’

and attributed to low cerebral blood flow (CBF). But, is every WMH at the end of a diseased

arteriole?

2

We examined scans of all our patients with acute lacunar stroke in the previous four years

and found a similar arteriole appearance in the symptomatic recent lacunar infarct in about

10%.1 Detailed examination of the few papers on lacunar stroke pathology was informative,

particularly C Miller Fisher’s meticulous dissections of the perforating arterioles leading to

lacunar strokes in the 1950s and 1960s.6, 7 Reading original observations is always valuable,

since subsequent interpretations may drift from the original over time. Fisher described the

arterioles in and around lacunes in four patients with hypertension and small strokes in life

as ‘segmental arteriolar disorganisation’ consisting of local dilatation and narrowing of the

arteriole, thickened disintegrating wall, and leakage of fibrinoid material and blood into and

around the wall. Others have called this process ‘fibrinoid necrosis’ or ‘hyalinosis’ amongst

other names. Interestingly, some of his histological images of the arteriolar pathology looked

similar to our ‘macroscopic’ MRI images (Figure 1).

Not just midlife atheroma or vascular risk factors.Much has been written about the causes of lacunar stroke and its distinct clinical syndromes

pointing to an intrinsic process,8 yet embolic processes and atheroma remain strong in

stroke thinking. Fisher’s lesions were mostly not embolic, but they might have been a ‘micro-

atheroma’ and MCA atheroma can obstruct the ostea of perforating arterioles. However,

much research, from large epidemiological to small intensive studies, confirms a lack of

direct association between embolic sources or atheroma and most small subcortical infarcts5,

9 or WMH.10-13 Consistent with this, long term intensive versus single antiplatelet agents not

only did not prevent recurrent lacunar stroke in the 3000+ patient Secondary Prevention of

Small Subcortical Stroke (SPS3) trial, but found that long-term dual antiplatelet drugs were

hazardous.14

Furthermore, although hypertension is a major risk factor for stroke, including lacunar

stroke,9 it and other common vascular risk factors are not the only cause. For example, in

about 750 community-dwelling subjects aged 72, and separately in about 150 patients with

non-disabling ischaemic stroke, all common vascular risk factors combined (hypertension,

smoking, diabetes, hypercholesterolaemia, measured blood pressure, cholesterol, HbA1c),

accounted for less than 2% of the variance in WMH burden.12 Of this 2%, hypertension and

smoking were the strongest risk factors. The unavoidable conclusion is that 98%, ie most, of

the variance in WMH is not explained by common vascular risk factors, also consistent with

the SPS3 trial in which intensive (versus guideline) blood pressure reduction did not prevent

recurrent stroke, WMH progression, or cognitive decline, in over 3000 patients with lacunar

stroke.15

3

These results do not mean that common vascular risk factor avoidance is not important. On

the contrary, it is very important. However, it does mean that the search for modifiable risk

factors should extend beyond conventional concurrent vascular risk factors, the main

message being that lacunar stroke and SVD are not simply a ‘small’ version of large artery

cardio-athero-thrombo-embolic stroke.

SVD risk occurs across the life-spanWhat might account for this unexplained 98% of SVD variance? The high heritability of at

least two common SVD features, WMH16 and perivascular spaces (PVS)17 indicate that

genes are important, yet genetic studies have so far identified relatively few SVD-related

genes. However, their detailed discussion is beyond the scope of this short paper which

focuses on unravelling SVD pathophysiological pathways through direct human studies.

Since SVD develops in the brain over many years, long before the lacunar stroke or

cognitive decline starts, what about risk-factors earlier in adulthood? Long-term adult lifestyle

habits, such as taking less exercise18 and more dietary salt,19, 20 are associated

independently with more WMH and lacunar (vs non-lacunar) ischemic stroke. The overall

health benefits of exercise, and detrimental effects of dietary salt, are well established, but

their specific effects on brain microvascular health are less appreciated. These invite public

health approaches to preventing SVD, since that will help prevent dementia as well as

stroke.

What about factors occurring even earlier in life? Interestingly, a large published literature

indicates that lower childhood intelligence, socioeconomic status and educational attainment

each predict increased lifetime risk of all types of SVD lesions,21 as well as stroke,22

independent of adult risk factors. Since these three factors are inter-related, and few studies

which examined all three simultaneously, their independent contribution to SVD or stroke

risk is unclear. However, the magnitude of effect of any one of them is similar and important

on a population basis. For example, expect 3.5/1000 more strokes in those who completed

full-time education to high school level versus those with university education,22 or 17%

relative increase in SVD lesions21 for the same education difference, moving responsibility

for stroke and SVD prevention from purely medical or public health onto Government

policies.

Consider the blood-brain barrier

4

Sporadic SVD is a complex disorder that develops over many years. While genetics,

childhood factors and adult lifestyle may raise the SVD risk, they do not explain what

actually goes wrong. The pathology described by Miller Fisher and others tends to reflect

late stage features,7 but preventing development or progression requires consideration of the

earliest disease stages. A possible unifying hypothesis to explain all three odd features

observed in our original case, was dysfunction of the endothelium and subtle blood-brain

barrier (BBB) leakage.23 If there was leakage, then it would have to be subtle, otherwise it

would have been obvious given the widespread clinical use of contrast-enhanced brain

imaging.

In studies including about 3000 subjects up to the mid 2000s, BBB leak, mostly detected

using the CSF:plasma albumin ratio, increased with age, was worse in any dementia versus

healthy controls, in vascular versus Alzheimer’s disease, and in patients with more WMH.24

However the CSF:plasma albumin ratio could not locate or quantify the leakage.

We developed methods to image subtle BBB leakage using dynamic contrast-enhanced MRI

with intravenous gadolinium and sequential T1 MRI seeking increased tissue and CSF

signal.25, 26 Gradually, as MRI and image processing improved, scan times shortened and

methods to calculate permeability improved.27 The details are beyond the scope of the

present paper, but suffice to note that the methods are complex, involving correction for

several factors (pre-contrast tissue T1,28 haematocrit,27 repeated measures to overcome

background noise, a reliable estimate of vascular input function27) and detailed image

processing that avoids tissue cross-contamination especially by large vessels.28 Despite this,

all current ‘permeability’ calculations rely on several assumptions, including that microvessel

density and surface area do not change with age, disease, or tissue type (clearly untrue).

Thus careful between-group comparisons of signal change to assess ‘leak’ may be safer.

Accumulating human cross-sectional analyses indicate that BBB leakage increases with

age, in lacunar vs non-lacunar stroke, with increasing visibility of PVS,25 in WMH versus

apparently normal tissue,29, 30 close to WMH in normal appearing tissue,3, 30 with increasing

WMH in normal appearing white matter,3, 31 in the hippocampus with cognitive impairment,32

in white matter in Alzheimer’s disease,33 and vascular dementia.29, 34, 35 Furthermore, in

longitudinal studies, BBB leakage predicts recurrent stroke, worsening of WMH,36 and

cognitive decline in patients with lacunar stroke.30

Might a leaky arteriole and increased periarteriolar interstitial fluid also explain the location of

the ‘infarct’ around, rather than at the end of, the arteriole in our patient with acute lacunar

5

stroke? Perhaps the ‘infarct’ is increased extracellular fluid, not just ischaemia, a speculation

that needs more research. Unfortunately the chances of scanning someone just before they

develop a lacunar stroke are remote, although there is one example: a patient had

gadolinium-enhanced MRI the day prior to presenting with a lacunar stroke; examination

showed gadolinium enhancement in the thalamus where the stroke developed.37

Further evidence for BBB leak comes from sensitive MRI methods that show that increased

interstitial fluid present in WMH, before demyelination and axonal loss typically seen

pathologically.3, 38-40 This observation is further strengthened by other recent work showing

raised tissue water, eg in skeletonised white matter mean diffusivity, to be the most sensitive

marker of cognitive impairment in patients with white matter disease.39

Why the discrepancy between MRI and pathology? They are sensitive to different factors:

conventional MRI relies on hydrogen, a major component of water, so is very sensitive to

shifting water content; pathology generally removes water from the specimen during

processing leaving rarefied axons visible, in part explaining why WMH until recently were

conventionally thought to indicate demyelination and axonal loss.

What about ischemia?If WMH are areas of increased fluid, what role does CBF play? In upwards of 10 cross-

sectional studies so far, in about 400 subjects, resting CBF is lower in people with more

versus less WMH (standardised mean difference, SMD: -0.73, 95%CI -1.16, -0.31).41

However, many studies did not have age-matched controls, or included patients with

Alzheimer’s disease. Excluding patients with Alzheimer’s dementia renders the CBF-WMH

association non-significant (SMD: -0.32, 95%CI -0.67, 0.02); focusing on studies with age-

matched controls removes any residual CBF-WMH association (SMD: -0.78, 95%CI -2.04,

0.49).41 What does this mean? Are WMH ‘ischaemic’ or not, or might the falling CBF reflect

having less brain to supply, perhaps explaining the association with Alzheimer’s disease a

classic feature of which is brain atrophy? The six longitudinal studies of WMH and CBF to

date, overall show that low baseline CBF does not lead to increasing WMH burden; instead,

a high WMH burden at baseline leads to falling CBF at follow-up,41, 42 suggesting the

reduction in CBF reflects having less brain to supply.

Resting CBF may not reflect CBF during brain activity. The brain has a highly responsive

vascular system designed to match the complex, rapid demands for increased oxygen,

glucose and removal of metabolic waste, the failure of which results rapidly in neurological

dysfunction. Cerebrovascular vasoreactivity (CVR), measured with Doppler ultrasound in the

6

MCA, falls with age and is worse in patients with stroke, and in lacunar versus non-lacunar

stroke, or with more WMH.43 To measure individual tissue-level vasoreactivity requires

techniques such as blood oxygen level dependent (BOLD) MRI,44 although results of most

studies to date are limited by not adjusting for age or hypertension.45 In 60 patients with

varied severities of WMH, CVR fell independently with increasing WMH and basal ganglia

PVS visibility,46 and CVR was not related to resting CBF but was related to increased

intracranial vascular pulsatility. Increased intracranial pulsatility was also related to increased

WMH and PVS visibility. These findings concur with the established relationship between

systemic arterial pulse pressure, which is strongly associated longitudinally with increased

WMH and PVS, independent of BP,47 and implicates impaired CVR and vessel stiffness in

the endothelial dysfunction contributing to SVD pathogenesis (Figure 2).

PVS deserve further mention. Visible on MRI as thin linear or round CSF-intensity structures

parallel with perforating microvessels, they are important conduits for brain interstitial fluid

balance, waste management and immune competence. Their enlargement (best seen on T2

or T1 MRI) is associated with hypertension, inflammation, BBB leakage, increased WMH,

and lacunar stroke. Close inspection of T2 and FLAIR MRI shows deep WMH forming

around PVS, consistent with growing evidence above on BBB leak25 and implying impaired

interstitial fluid drainage in SVD pathogenesis (Figure 2).

Rodent studies suggest that tissue clearance and drainage via PVS may increase during

sleep,48 although the results are controversial. However, increased clearance of metabolites

would perhaps explaining the importance of sleep to brain health.

Small vessel brain damage is permanent?The assumption that SVD features are due to ischemia and demyelination implies that the

lesions represent end stage, permanent damage. However, two recent studies demonstrate

that WMH can shrink, and even lacunes and microbleeds can disappear.49, 50 We followed

200 subjects to one year after non-disabling ischemic stroke and found that WMH volume

clearly decreased in about 20%, increased in about 20% and either did not change at all or

only by a small amount in the remainder.49 Reduction in WMH volume was associated with

fewer recurrent neurological events and contemporaneous reduction in brain water content

on MRI, supporting that the WMH change was real, not measurement error. The RUN DMC

study during 10 years of follow-up found lacunes, microbleeds and WMH forming and

disappearing.50 It appears that the pathology underlying SVD is not permanent and lesions

are much more dynamic than previously thought.

7

What to do?What can be done to prevent or correct subtle BBB leakage, stiff vessels and poor

vasoreactivity? Might any current therapies, licenced for other purposes but with relevant

modes of action, be helpful? There are many established cardiovascular drugs with relevant

effects, which might also help mitigate the cognitive effects of SVD, thereby addressing a

huge unmet societal burden of dementia and stroke, buying time for more specific novel

agents to be developed.

A detailed literature search identified several agents with potentially relevant modes of

action, of which two oral agents had the most encouraging human data: isosorbide

mononitrate (ISMN) and cilostazol.51 The animal literature supported the same conclusion.52

Why these two drugs? Most importantly, they are both widely used, have known safety

profiles, and limited but encouraging data in lacunar stroke.

ISMN, a nitric oxide (NO) donor. NO is reduced in acute, chronic and possibly lacunar

stroke; given acutely after stroke, NO donors improved cognitive test scores at 90 days in

the 4000-patient ENOS trial.53 NO has multiple potentially beneficial effects for SVD

including improved blood-brain barrier integrity, vasodilation, reducing inflammation, and

neuroprotection,51, 54 although data on ISMN in lacunar stroke are sparse since ischemic

heart disease (its main therapeutic indication) is uncommon in these patients.9

Cilostazol, a phosphodiesterase 3’ inhibitor, has multiple potential relevant beneficial effects,

including that: in humans, it improved blood-brain barrier integrity and vasodilation, reduced

vessel stiffness55 and inflammation;51 in models, it improved motor/cognitive function,

reduced infarct volume, increased myelin repair via improved oligodendrocyte precursor cell

maturation and astrocyte-to-neuronal energy transfer.56 Cilostazol trials include over 6000

patients in Japan, Korea and China, many with lacunar stroke, but cilostazol is little used in

Europe or North America.

Since both ISMN and cilostazol combined may be synergistic, they are being tested

factorially in the LACunar Intervention (LACI) trials: LACI-1 (ISRCTN12580546), recruited 57

patients in two centres to test short-term tolerability, safety, intermediary endpoints and trial

feasibility;57 LACI-2 (ISRCTN14911850), planned n=400 in 20 centres, now ongoing, tests

longer-term tolerability, trial feasibility, safety and efficacy on patient relevant outcomes

preparatory to large phase III trials.

8

More generally, hypertension is common in lacunar stroke. Some antihypertensive drugs

may have more relevant endothelial effects, and BP targets remain unclear especially in

frailer older people, providing ongoing justification for trials (e.g. PRESERVE,

TREAT@SVDs) testing specific antihypertensive strategies in specific patient populations.

Other agents such as allopurinol also have relevant vascular effects and are being tested

(e.g. XYLOFIST).

Meanwhile, general advice to patients should include common sense: stop smoking, take

regular exercise, eat a well-balanced diet, avoid excess dietary salt, and adhere to

prescribed treatment for hypertension, hypercholesterolemia and diabetes where relevant.

The futureSVD is not silent, permanent, or untreatable. Importantly, advances made in recent years

open new insights, offering new therapeutic targets. SVD is a common cause of stroke and

worsens all stroke outcomes. As Hachinksi has said, the commonest form of

cerebrovascular disease is dementia not stroke, vascular dementia is the second

commonest dementia with SVD as the commonest cause, vascular dysfunction occurs early

in Alzheimer’s disease, and dementia prevention and treatment are currently very limited, yet

many drugs with known vascular effects might prevent or delay progression of dementia.

Stroke, dementia and cardiovascular experts should combine their strengths since a united

approach offers hope not just for stroke but also for dementia.

9

AcknowledgementsI am grateful to the many mentors, clinical and science colleagues and early stage

researchers with whom I have been fortunate to work over many years, whose collective

thoughts have contributed to this work. I was very privileged to receive the William M

Feinberg award in the company of many of them and the wider stroke community that

continues to work tirelessly towards mitigating the personal and societal global burden of

cerebrovascular disease.

FundingThe work described was funded by the Chief Scientist Office (CZB/4/281), Wellcome Trust

(WT088134/Z/09/A), the Row Fogo Charitable Trust (BRO-D.FID3668413), Chest Heart

Stroke Scotland (Res14/A157), Medical Research Council (G0701120, G1001245,

MR/M013111/1, MR/K026992/1), AgeUK, Alzheimer Society (AS-PG-14-033), EU Horizon

2020, (PHC-03-15, No 666881), Fondation Leducq (16 CVD 05).

DisclosuresNone.

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FiguresFigure 1. CT (A) and MR (B sagittal T1, C axial T2, D axial T2*) images from a 70 year old

man who presented shortly after a left hemisphere lacunar syndrome (adapted from

Wardlaw et al, Ann Neurol 2001, Fig 1,1 publ. John Wyllie and Sons, with permission, license

number 4351401429541). Note the ‘infarct’ (arrows, A) with the central hyperattenuated ‘dot’

in cross-section like a ‘mini hyperattenuated artery sign’; this appears linear on the sagittal

T1 (B) consistent with the orientation of the perforating arteriole. The arteriole wall appears

thickened with blood signal within it (C, D) particularly striking on the T2* blood-sensitive

sequence (D). The ‘infarct’ is around about the mid arteriole, not at its end. A tiny side

branch is visible in D (short arrow).

Figure 2. Diagram illustrating dynamic relationships between small vessel function, and SVD

lesions. A, Resting CBF is weakly related to intracranial vascular pulsatility but not to

cerebrovascular reactivity while increasing pulsatility is strongly related to declining

cerebrovascular reactivity. B, falling CBF is not related to WMH or PVS severity, but both

increasing pulsatility and falling cerebrovascular reactivity are associated with increased

WMH and PVS. C, Close inspection of FLAIR (top) and T2-weighted (bottom) MRI shows

that WMH form around PVS.

11

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